Radical Approach to Enzymatic β-Thioether Bond Formation.

TitleRadical Approach to Enzymatic β-Thioether Bond Formation.
Publication TypeJournal Article
Year of Publication2019
AuthorsCaruso, A, Bushin, LB, Clark, KA, Martinie, RJ, Seyedsayamdost, MR
JournalJ Am Chem Soc
Volume141
Issue2
Pagination990-997
Date Published2019 01 16
ISSN1520-5126
KeywordsAmino Acid Sequence, Bacterial Proteins, Carbon-Sulfur Lyases, Models, Chemical, Multigene Family, Peptide Biosynthesis, Peptides, Protein Processing, Post-Translational, S-Adenosylmethionine, Streptococcus, Sulfides
Abstract

Ribosomally synthesized and post-translationally modified peptides (RiPPs) are an emerging class of natural products that harbor diverse chemical functionalities, usually introduced via the action of a small number of tailoring enzymes. We have been interested in RiPP biosynthetic gene clusters that encode unusual metalloenzymes, as these may install as yet unknown alterations. Using a new bioinformatic search strategy, we recently identified an array of unexplored RiPP gene clusters that are quorum sensing-regulated and contain one or more uncharacterized radical S-adenosylmethionine (RaS) metalloenzymes. Herein, we investigate the reaction of one of these RaS enzymes and find that it installs an intramolecular β-thioether bond onto its substrate peptide by connecting a Cys-thiol group to the β-carbon of an upstream Asn residue. The enzyme responsible, NxxcB, accepts several amino acids in place of Asn and introduces unnatural β-thioether linkages at unactivated positions. This new transformation adds to the growing list of Nature's peptide macrocyclization strategies and expands the already impressive catalytic repertoire of the RaS enzyme superfamily.

DOI10.1021/jacs.8b11060
Alternate JournalJ. Am. Chem. Soc.
PubMed ID30521328